Sara Horst, MD, on IL-12/23 and IL-23 Receptor Antagonists for Treatment of IBD

Dr Horst recaps her presentation from the Advances in Inflammatory Bowel Diseases regional meeting on using IL-12/23 and IL-23 receptor antagonists in treating IBD.

Sara Horst, MD, is a gastroenterologist with the Vanderbilt University Medical Center IBD Clinic in Nashville, Tennessee.

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TRANSCRIPT:

Sarah Horst:

Hi, I'm Sarah Horst, a gastroenterologist at Vanderbilt University Medical Center and I specialize in the care of patients with inflammatory bowel disease. I was really excited to be able to talk about the topic of IL-12/23 and IL-23 receptor antagonists at the recent AIBD Regional Course. This is a really exciting topic. And I think over the next few years, we're going to see a lot more interesting outcomes for and options for our patients with inflammatory bowel disease.

When we think about IL-12 and IL-23 receptor antagonism, it's important to think about the back structure and the way that these work. The option that we have on the market currently is an IL-12/23 receptor antagonist and this binds to the p40 subunit of both of these cytokines. There are receptor antagonists available for other disease states and probably coming soon for patients with inflammatory bowel disease, which are IL-23 receptor antagonists only. This binds the p19 subunit of IL-23.

And why is this important? Well, when people were first looking at IL-12 and inflammation, it was thought that it was really this IL-12 that was the driver of inflammation. And so, the p40 subunit was targeted. However, in the early 2000s, it was discovered that there was another cytokine, IL-23, that had this p40 subunit. And as further basic science and really elegant research went into this, it was discovered that probably IL-23 may be a driver of real, the big driver of inflammation in patients with inflammatory bowel disease.

It may be driving more of the Th17 response going down a JAK/STAT pathway, which is promoting pro-inflammatory cytokines that we know are involved in inflammatory bowel disease. So it's very interesting to think about IL-12/23 receptor antagonism versus just IL-23 alone. There are IL-23 receptor antagonists likely coming into the treatment arena in the next few years. That'll be exciting to see really whether this additional differentiation results in improved patient outcomes or not.

There are some studies in psoriasis that may suggest this. In thinking about what we have available now, we have ustekinumab, which really has some very good treatment clinical response and remission when you look at their phased clinical trials in unity for patients with Crohn's disease. And more recently, approval in ulcerative colitis. I think it's really important when we think about ustekinumab to remember that there's a new study, a head-to-head clinical trial, the CDU study that looked at randomized monotherapy for bio-naive patients.

And looked at it compared to anti-TNF medications, specifically Adalimumab and really found no difference between the endpoints. Similar rates of clinical response, high rates of clinical response with both of these medications. It's really a great new option for patients. It also has a great safety profile, really no increased risk of serious infections. It has much lower rates of immunogenicity when we think about comparing to things, to other biologics. SI think as we think about positioning over time, these medications may be moving up or down.

When we look at network meta-analysis, it really still is a bit behind in Crohn's disease, behind anti-TNF. But when we think about second-line therapy, it seems to... IL-12/23 receptor antagonism seems to be really coming to the forefront as options for treatment. We also have new strategies coming. IL-23 receptor antagonists only. And there are at least four that are in phase two and three clinical trials. Rituximab, [inaudible 00:04:26] and mirikizumab that are coming onto the market and are really exciting options for us to think about in the future.

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